Movement disorders can generally be classified into two categories: hyperkinetic movement disorders and hypokinetic movement disorders. Hyperkinetic movement disorders are caused by an increase in muscular activity and can cause abnormal and/or excessive movements, including tremors, dystonia, chorea, tics, myoclonus and stereotypies.
Hyperkinetic movement disorders often are often psychological in nature and arise through improper regulation of amine neurotransmitters in the basal ganglia.
Tourette's syndrome is an inherited neurological condition characterised by multiple physical and vocal tics. The tics are usually repetitive, but random, physical movements or vocal noises. The vocal tics can be of various forms and include repeating one's own words, the words of others or other sounds. Onset usually occurs in children and continues through to adolescence and adulthood.
While the tics associated with Tourette's syndrome are temporarily suppressible, those affected can usually only suppress their tics for limited time periods. There is yet to be an effective treatment to cover all types of tics in all patients, but certain medicaments for tic suppression have been developed.
It is known that dopamine receptor antagonists display an ability to suppress tics in Tourette's syndrome patients and a number dopamine receptor antagonists are currently used in the suppression of Tourette's tics, such as fluphenazine, risperidone, haloperidol and pimozide.
Type 2 vesicular monoamine transporter (VMAT2) is a membrane protein responsible for the transportation of monoamine neurotransmitters, such as dopamine, serotonin and histamine, from cellular cytosol into synaptic vesicles. Inhibition of this protein hinders presynaptic neurons from releasing dopamine, resulting in a depletion of dopamine levels in the brain.
It is therefore to be expected that VMAT2 inhibitors may be effective agents against the symptoms of Tourette's syndrome.
Tetrabenazine (Chemical name: 1,3,4,6,7,11b-hexahydro-9,10-dimethoxy-3-(2-methylpropyl)-2H-benzo(a)quinolizin-2-one) has been in use as a pharmaceutical drug since the late 1950s. Initially used as an anti-psychotic, tetrabenazine is currently used for treating hyperkinetic movement disorders such as Huntington's disease, hemiballismus, senile chorea, tic, tardive dyskinesia and Tourette's syndrome, see for example Jankovic et al., Am. J. Psychiatry. (1999) August; 156(8):1279-81 and Jankovic et al., Neurology (1997) February; 48(2):358-62.
The primary pharmacological action of tetrabenazine is to reduce the supply of monoamines (e.g. dopamine, serotonin, and norepinephrine) in the central nervous system by inhibiting the human vesicular monoamine transporter isoform 2 (hVMAT2). The drug also blocks postsynaptic dopamine receptors.
Tetrabenazine is an effective and safe drug for the treatment of a variety of hyperkinetic movement disorders and, in contrast to typical neuroleptics, has not been demonstrated to cause tardive dyskinesia. Nevertheless, tetrabenazine does exhibit a number of dose-related side effects including causing depression, parkinsonism, drowsiness, nervousness or anxiety, insomnia and, in rare cases, neuroleptic malignant syndrome.
The central effects of tetrabenazine closely resemble those of reserpine, but it differs from reserpine in that it lacks activity at the VMAT1 transporter. The lack of activity at the VMAT1 transporter means that tetrabenazine has less peripheral activity than reserpine and consequently does not produce VMAT1-related side effects such as hypotension.
The chemical structure of tetrabenazine is as shown below.

The compound has chiral centres at the 3 and 11b carbon atoms and hence can, theoretically, exist in a total of four isomeric forms, as shown below.

The stereochemistry of each isomer is defined using the “R and S” nomenclature developed by Cahn, Ingold and Prelog, see Advanced Organic Chemistry by Jerry March, 4th Edition, John Wiley & Sons, New York, 1992, pages 109-114. In this patent application, the designations “R” or “S” are given in the order of the position numbers of the carbon atoms. Thus, for example, RS is a shorthand notation for 3R,11bS. Similarly, when three chiral centres are present, as in the dihydrotetrabenazines described below, the designations “R” or “S” are listed in the order of the carbon atoms 2, 3 and 11b. Thus, the 2R,3S,11bS isomer is referred to in short hand form as RSS and so on.
Commercially available tetrabenazine is a racemic mixture of the RR and SS isomers and it would appear that the RR and SS isomers are the most thermodynamically stable isomers.
Tetrabenazine has somewhat poor and variable bioavailability. It is extensively metabolised by first-pass metabolism, and little or no unchanged tetrabenazine is typically detected in the urine. It is known that at least some of the metabolites of tetrabenazine are dihydrotetrabenazines formed by reduction of the 2-keto group in tetrabenazine.
Dihydrotetrabenazine (Chemical name: 2-hydroxy-3-(2-methylpropyl)-1,3,4,6,7,11b-hexahydro-9,10-dimethoxy-benzo(a)quinolizine) has three chiral centres and can therefore exist in any of the following eight optical isomeric forms:

The synthesis and characterisation of all eight dihydrotetrabenazine isomers is described by Sun et al. (Eur. J. Med. Chem. (2011), 1841-1848).
Of the eight dihydrotetrabenazine isomers, four isomers are derived from the more stable RR and SS isomers of the parent tetrabenazine, namely the RRR, SSS, SRR and RSS isomers.
The RRR and SSS isomers are commonly referred to as “alpha (α)” dihydrotetrabenazines and can be referred to individually as (+)-α-dihydrotetrabenazine and (−)-α-dihydrotetrabenazine respectively. The alpha isomers are characterised by a trans relative orientation of the hydroxyl and 2-methylpropyl substituents at the 2- and 3-positions—see for example, Kilbourn et al., Chirality, 9:59-62 (1997) and Brossi et al., Helv. Chim. Acta., vol. XLI, No. 193, pp 1793-1806 (1958).
The SRR and RSS isomers are commonly referred to as “beta (β)” isomers and can be referred to individually as (+)-β-dihydrotetrabenazine and (+β-dihydrotetrabenazine respectively. The beta isomers are characterised by a cis relative orientation of the hydroxyl and 2-methylpropyl substituents at the 2- and 3-positions.
Although dihydrotetrabenazine is believed to be primarily responsible for the activity of the drug, there have been no studies published to date that contain evidence demonstrating which of the various stereoisomers of dihydrotetrabenazine is responsible for its biological activity. More specifically, there have been no published studies demonstrating which of the stereoisomers is responsible for the ability of tetrabenazine to treat movement disorders such as Tourette's syndrome.
Schwartz et al. (Biochem. Pharmacol. (1966), 15: 645-655) describes metabolic studies of tetrabenazine carried out in rabbits, dogs and humans. Schwartz et al. identified nine metabolites, five of which were unconjugated and the other four of which were conjugated with glucuronic acid. The five unconjugated metabolites were the alpha- and beta-dihydrotetrabenazines, their two oxidised analogues in which a hydroxyl group has been introduced into the 2-methylpropyl side chain, and oxidised tetrabenazine in which a hydroxyl group has been introduced into the 2-methylpropyl side chain. The four conjugated metabolites were all compounds in which the 9-methoxy group had been demethylated to give a 9-hydroxy compound. The chirality of the various metabolites was not studied and, in particular, there was no disclosure of the chirality of the individual α- and β-isomers.
Scherman et al., (Mol. Pharmacol. (1987), 33, 72-77 describes the stereospecificity of VMAT2 binding between racemic α- and β-dihydrotetrabenazine. They reported that α-dihydrotetrabenazine had a 3- to 4-fold higher affinity for the Chromaffin Granule Monoamine Transporter than the β-isomer, when studied in vitro. However, Scherman et al. does not disclose the resolution or testing of the individual enantiomers of the α- and β-dihydrotetrabenazines.
Mehvar et al. (J. Pharm. Sci. (1987), 76(6), 461-465) reported a study of the concentrations of tetrabenazine and dihydrotetrabenazine in the brains of rats following administration of either tetrabenazine or dihydrotetrabenazine. The study showed that despite its greater polarity, dihydrotetrabenazine was able to cross the blood-brain barrier. However, the stereochemistry of the dihydrotetrabenazine was not disclosed.
Mehvar et al. (Drug Metabolism and Disposition (1987), 15:2, 250-255) describes studies of the pharmacokinetics of tetrabenazine and dihydrotetrabenazine following administration of tetrabenazine to four patients affected by tardive dyskinesia. Oral administration of tetrabenazine resulted in low plasma concentrations of tetrabenazine but relatively high concentrations of dihydrotetrabenazine. However, the stereochemistry of the dihydrotetrabenazine formed in vivo was not reported.
Roberts et al. (Eur. J. Clin. Pharmacol. (1986), 29: 703-708) describes the pharmacokinetics of tetrabenazine and its hydroxy-metabolite in patients treated for involuntary movement disorders. Roberts et al. reported that tetrabenazine was extensively metabolised after oral administration resulting in very low plasma concentrations of tetrabenazine but much higher concentrations of a hydroxy-metabolite. Although they did not describe the identity of the hydroxy-metabolites, they suggested that the high plasma concentrations of the hydroxy-metabolites may be therapeutically important (since the metabolites were known to be pharmacologically active) and that, in view of the disclosure in Schwartz et al. (idem), the combination of cis and trans isomers (i.e. beta and alpha isomers) could be more therapeutically important than the parent drug.
Michael Kilbourn and collaborators at the University of Michigan Medical School have published a number of studies relating to the various isomers of dihydrotetrabenazines. In Med. Chem. Res. (1994), 5:113-126, Kilbourn et al. describe the use (+/−)-α-[11C]-dihydrotetrabenazine as in vivo imaging agents for VMAT2 binding studies.
In Eur. J. Pharmacol (1995) 278, 249-252, Kilbourn et al. reported competition binding studies using [3H]-tetrabenazine to study the in vitro binding affinity of (+)-, (−)-, and (+/−)-α-DHTBZ. The binding assays gave a Ki value of 0.97 nM for (+)-α-dihydrotetrabenazine and 2.2 μM for (−)-α-dihydrotetrabenazine, thereby showing that the (+) alpha isomer has much greater binding affinity for the VMAT2 receptor than the (−) alpha isomer. However, no studies were reported, or conclusions drawn, as to the usefulness of either isomer in the treatment of movement disorders such as Tourette's syndrome.
In Chirality (1997) 9:59-62, Kilbourn et al. described studies aimed at identifying the absolute configuration of (+)-α-dihydrotetrabenazine from which they concluded that it has the 2R, 3R, 11bR configuration shown above. They also referred to the Schwartz et al. and Mehvar et al. articles discussed above as indicating that the α- and β-dihydrotetrabenazines are likely to be the pharmacologically active agents in the human brain but they drew no explicit conclusions as to the precise stereochemical identities of the active metabolites of tetrabenazine.
In Synapse (2002), 43:188-194, Kilbourn et al. described the use of (+)-α-[11C]-dihydrotetrabenazine as an agent used to measure specific in vivo binding of the VMAT receptor, in “infusion to equilibrium methods”. They found that (−)-α-[11C]-dihydrotetrabenazine produced a uniform brain distribution, consistent with the earlier observations that this enantiomer has a low VMAT affinity.
Sun et al. (idem) investigated the VMAT2 binding affinities of all eight dihydrotetrabenazine isomers. They found that all of the dextrorotatory enantiomers exhibited dramatically more potent VMAT2 binding activity than their corresponding laevorotatory enantiomers with the most active (+)-α-isomer being found to be the most active. However, Sun et al. did not carry out any investigations into the relative efficacies of the individual isomers in treating movement disorders such as Tourette's syndrome.
WO2015/120110 (Auspex) describes extended-release formulations that can contain any of a wide variety of different pharmacological agents, including tetrabenazine and dihydrotetrabenazine. However, there are no worked examples of any dihydrotetrabenazine formulations; but only formulations containing tetrabenazine.
WO 2011/153157 (Auspex Pharmaceutical, Inc.) describes deuterated forms of dihydrotetrabenazine. Many deuterated forms of dihydrotetrabenazine are depicted but the application only provides sufficient information to allow a small number of the depicted compounds to be synthesised. Although racemic mixtures of d6-α-dihydrotetrabenazine and d6-β-dihydrotetrabenazine are disclosed, these mixtures were not resolved and the properties of the individual (+) and (−) isomers were not studied. Similarly, WO 2014/047167 (Auspex Pharmaceutical, Inc.) describes a number of deuterated forms of tetrabenazine and its derivatives. Again, the individual (+) and (−) isomers of deuterated forms of α- and β-dihydrotetrabenazine were not separated or studied.
It appears therefore that, up to the present, it remains unclear as to precisely which dihydrotetrabenazine isomers are responsible for the therapeutic properties resulting from the administration of tetrabenazine.
It has also remained somewhat unclear up until now whether (+)-α-dihydrotetrabenazine will provide a therapeutically useful effect in the treatment of movement disorders such as Tourette's syndrome without the accompaniment of unwanted side effects such as those described above. Thus, for example, whereas WO2016/127133 (Neurocrine Biosciences) refers to the Kilbourn et al. article in Chirality (idem) as indicating that (+)-α-dihydrotetrabenazine is the active metabolite of tetrabenazine. WO2016/127133, it also refers to the studies reported in Login et al. (1982), Ann. Neurology 12:257-62 and Reches et al., J. Pharmacol. Exp. Ther. (1983), 225:515-521 which indicate that tetrabenazine inhibits presynaptic and postsynaptic dopamine receptors in the rat brain. It is suggested in WO2016/127133 that this “off-target” activity of tetrabenazine may be responsible for some of the observed side effects of tetrabenazine.
As discussed above, it is known that tetrabenazine exhibits a number of dose-related side effects including causing depression and parkinsonism (see WO2016/127133). It appears that these side-effects may also be caused by VMAT2 inhibition and that consequently it is difficult to separate the therapeutic effect of tetrabenazine and tetrabenazine-derived compounds from these side-effects (see Müller, “Valbenazine granted breakthrough drug status for treating tardive dyskinesia”, Expert Opin. Investig. Drugs (2015), 24(6), pp. 737-742).
In an attempt to avoid or reduce the side-effects associated with tetrabenazine, a valine ester prodrug of (+)-α-dihydrotetrabenazine has been developed, known by its INN name, Valbenazine. The structure of Valbenazine is shown below:

As disclosed in U.S. Pat. No. 8,039,627, Valbenazine is prepared by reacting (+)-α-dihydrotetrabenazine with carbobenzyloxy-L-valine in dichloromethane and 4-dimethylaminopyridine (DMAP) in the presence of N,N′-dicyclohexylcarbodiimide (DCC) to give the intermediate 2-benzyloxycarbonylamino-3-methyl-butyric acid (2R,3R,1bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester. The intermediate is then hydrogenated over palladium on carbon to remove the benzyloxycarbonyl protecting group to give Valbenazine.
Müller (“Valbenazine granted breakthrough drug status for treating tardive dyskinesia”, Expert Opin. Investig. Drugs (2015), 24(6), pp. 737-742) describes a Phase IIb clinical study of Valbenazine (“KINECT 1”) in patients suffering from tardive dyskinesia. Although some reduction of symptoms was observed when doses of Valbenazine at 100 mg/day were observed, subjects who received 50 mg/day of Valbenazine did not show any significant signs of improvement, when scored with the abnormal involuntary movement scale (AIMS). Müller concluded that this study was more or less a failure, probably due to low Valbenazine dosing.
In a further study (“KINECT 2”) described in the same paper, subjects were initially dosed at 25 mg/day, with the dose range increasing to 75 mg/day. By the end of the study, when measurements were taken, 21 out of 34 of the subjects treated with Valbenazine were being dosed at 75 mg/day (O'Brien et al, “Kinect 2: NBI-98854 treatment of moderate to severe tardive dyskinesia” Mov. Disord. 2014; 29 (Suppl 1):829). The analysis does not provide a breakdown of the reduction in abnormal involuntary movements in patients who were being treated with 75 mg/day by the end of the trial and those who were being treated with 25 mg/day or 50 mg/day by the end of the trial.
A further Phase III trial of Valbenazine, reported by O'Brien et al (“KINECT 3 A randomised, Double-Blind Placebo-Controlled Phase 3 Trial of Valbenazine (NBI-98854) for Tardive Dyskinesia (PL02.003)”, Neurology (2016), 86(16), Supplement PL02.003) investigated the change in abnormal involuntary movements in Tardive Dyskinesia sufferers when administered with 40 mg or 80 mg of Valbenazine per day. It was found that 80 mg/day of Valbenazine resulted in a significant improvement in the Abnormal Involuntary Movement Score and it was concluded that 80 mg/day Valbenazine was associated with a significant improvement in Tardive Dyskinesia.
WO 2015/171802 (Neurocrine Biosciences, Inc.) describes methods for treating hyperkinetic diseases by administering therapeutic agents that produce plasma concentrations of (+)-α-dihydrotetrabenazine such that there is a Cmax of between about 15 ng/ml and 60 ng/ml and a Cmin of at least 15 ng/ml over an eight hour period. Although it is suggested in WO 2015/171802 that this can be accomplished by administering (+)-α-dihydrotetrabenazine per se, the experiments described in WO 2015/171802 only provide data for (+)-α-dihydrotetrabenazine levels achieved after the administration of Valbenazine. In Example 1 of WO 2015/171802, it is concluded that a concentration of 30 ng/ml of (+)-α-dihydrotetrabenazine in plasma is an appropriate target and that exposures below 15 ng/ml are suboptimal across the general tardive dyskinesia (TD) population. In Example 2 of WO 2015/171802, it is disclosed that a 50 mg dose of Valbenazine appeared to maintain the required plasma levels of (+)-α-dihydrotetrabenazine.
WO2016/210180 (Neurocrine Biosciences) discloses the use of VMAT2 inhibitors for treating various neurological disorders. (+)-α-dihydrotetrabenazine is mentioned as an example of a VMAT2 inhibitor but he VMAT2 inhibitory compounds specifically exemplified in WO2016/210180 are Valbenazine and [(2R, 3S, 11bR)-9,10-dimethoxy-3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-yl]methanol.
Although having a greater solubility than tetrabenazine, (+)-α-dihydrotetrabenazine still possess a relatively low solubility and also demonstrates a tendency to form polymorphs. Therefore, there exists the need for pharmaceutical compositions of (+)-α-dihydrotetrabenazine with improved physical properties.
The Invention
(+)-α-Dihydrotetrabenazine salts are antagonists of VMAT2. Tetrabenazine exerts its therapeutic effects by inhibiting VMAT2 in the brain and by inhibiting both pre-synaptic and post-synaptic dopamine receptors.
The inventors of the present application have found that the (+)-α-dihydrotetrabenazine succinate salt possesses unexpectedly good physical properties in comparison with the free base and other common acid addition salts. In particular, the succinate salt has a higher solubility and a greater thermal stability, with a reduced tendency to form polymorphs, than the free base and other common salts.
On the basis of the studies carried out to date, it is envisaged that the succinate salt of (+)-α-dihydrotetrabenazine will be useful in the prophylaxis or treatment of the disease states and conditions for which tetrabenazine is currently used or proposed. Thus, by way of example, and without limitation, the (+)-α-dihydrotetrabenazine succinate salt of the invention may be used for the treatment of hyperkinetic movement disorders such as Huntington's disease, hemiballismus, senile chorea, tic disorders, tardive dyskinesia, dystonia and Tourette's syndrome. It is also envisaged that the dihydrotetrabenazine succinate salt of the invention may be useful in the treatment of depression.
(+)-α-Dihydrotetrabenazine is believed to have the chemical structure (I) shown in formula (I) below:

Accordingly, the invention provides (+)-α-dihydrotetrabenazine succinate, which has a chemical formula as shown in Formula (II).

In this application, (+)-α-dihydrotetrabenazine succinate may be referred to for convenience and brevity as (+)-α-DHTBZ succinate or (+)-α-DHTBZ succinate salt, or the succinate salt of the invention.
The succinate salt of the invention typically has a salt ratio (molar ratio of (+)-α-dihydrotetrabenazine free base to the acid) of approximately 1:1.
In another aspect, the invention provides a pharmaceutical composition comprising (+)-α-dihydrotetrabenazine succinate and a pharmaceutically acceptable excipient.
The invention also provides:                (+)-α-dihydrotetrabenazine succinate for use in medicine.        (+)-α-dihydrotetrabenazine succinate for use as a VMAT2 receptor antagonist.        (+)-α-Dihydrotetrabenazine succinate for use in the treatment of a movement disorder (e.g. a hyperkinetic movement disorder).        A method of treatment of a movement disorder (e.g. a hyperkinetic movement disorder) in a subject in need thereof (e.g. a mammalian subject such as a human), which method comprises administering to the subject a therapeutically effective amount of (+)-α-dihydrotetrabenazine succinate.        The use of (+)-α-dihydrotetrabenazine succinate for the manufacture of a medicament for the treatment of a movement disorder (e.g. a hyperkinetic movement disorder).        A unit dosage form (for example a capsule or a tablet) comprising (+)-α-dihydrotetrabenazine succinate and a pharmaceutically acceptable excipient.        
The (+)-α-dihydrotetrabenazine succinate may be used in the treatment of a hyperkinetic movement disorder such as Huntington's disease, hemiballismus, senile chorea, tic disorders, tardive dyskinesia, dystonia and Tourette's syndrome. In one embodiment, the hyperkinetic movement order is Tourette's syndrome.
The (+)-α-dihydrotetrabenazine succinate described herein typically has an isomeric purity of greater than 60%.
The term “isomeric purity” in the present context refers to the amount of (+)-α-dihydrotetrabenazine free base present in the succinate salt relative to the total amount or concentration of dihydrotetrabenazine of all isomeric forms. For example, if 90% of the total dihydrotetrabenazine present in the composition is (+)-α-dihydrotetrabenazine, then the isomeric purity is 90%.
The (+)-α-dihydrotetrabenazine salt of the invention may have an isomeric purity of greater than 82%, greater than 85%, greater than 87%, greater than 90%, greater than 91%, greater than 92%, greater than 93%, greater than 94%, greater than 95%, greater than 96%, greater than 97%, greater than 98%, greater than 99%, greater than 99.5%, or greater than 99.9%.
The (+)-α-dihydrotetrabenazine succinate will generally be administered to a subject in need of such administration, for example a human or animal patient, preferably a human.
The (+)-α-dihydrotetrabenazine succinate will typically be administered in amounts that are therapeutically or prophylactically useful and which generally are non-toxic. However, in certain situations, the benefits of administering a dihydrotetrabenazine compound of the invention may outweigh the disadvantages of any toxic effects or side effects, in which case it may be considered desirable to administer compounds in amounts that are associated with a degree of toxicity.
The inventors of the present application have also found that that (+)-α-dihydrotetrabenazine is effective in the treatment of movement disorders (e.g. a hyperkinetic movement disorder) at much lower doses than could have been predicted from the literature (for example from WO 2015/171802) and that its use at such lower doses can avoid or minimize the unwanted side effects associated with tetrabenazine.
More particularly, experiments carried out by the present inventors indicate that movement disorders such as Tourette's syndrome can be treated effectively by administering much lower doses of (+)-α-dihydrotetrabenazine per se than the doses of Valbenazine required in WO 2015/171802.
Accordingly, in another aspect, the invention provides a pharmaceutical composition comprising (+)-α-dihydrotetrabenazine succinate and a pharmaceutically acceptable excipient.
The pharmaceutical composition can be, for example, a unit dosage form comprising from 0.5 mg to 30 mg (e.g. between 0.5 mg and 20 mg) of (+)-α-dihydrotetrabenazine succinate and a pharmaceutically acceptable excipient.
The unit dosage form can be one which is administered orally, for example a capsule or tablet.
In particular embodiments of the invention, there is provided:                A unit dosage form comprising from 0.5 mg to 30 mg (e.g. between 0.5 mg and 30 mg) of (+)-α-dihydrotetrabenazine succinate and a pharmaceutically acceptable excipient.        A unit dosage form comprising from 0.5 mg to 25 mg (e.g. between 0.5 mg and 25 mg) of (+)-α-dihydrotetrabenazine succinate and a pharmaceutically acceptable excipient.        A unit dosage form comprising from 0.5 mg to 20 mg (e.g. between 0.5 mg and 20 mg) of (+)-α-dihydrotetrabenazine succinate and a pharmaceutically acceptable excipient.        A unit dosage form comprising from 1 mg to 30 mg (e.g. between 1 mg and 30 mg) of (+)-α-dihydrotetrabenazine succinate and a pharmaceutically acceptable excipient.        A unit dosage form comprising from 1 mg to 25 mg (e.g. between 1 mg and 25 mg) of (+)-α-dihydrotetrabenazine succinate and a pharmaceutically acceptable excipient.        A unit dosage form comprising from 1 mg to 20 mg (e.g. between 1 mg and 20 mg) of (+)-α-dihydrotetrabenazine succinate and a pharmaceutically acceptable excipient.        A unit dosage form comprising from 2 mg to 20 mg (e.g. between 2 mg and 20 mg) of (+)-α-dihydrotetrabenazine succinate and a pharmaceutically acceptable excipient.        A unit dosage form comprising from 0.5 mg to 10 mg (e.g. between 0.5 mg and 10 mg) of (+)-α-dihydrotetrabenazine succinate and a pharmaceutically acceptable excipient.        A unit dosage form comprising from 0.5 mg to 7.5 mg (e.g. between 0.5 mg and 7.5 mg) of (+)-α-dihydrotetrabenazine succinate and a pharmaceutically acceptable excipient.        A unit dosage form comprising from 1 mg to 10 mg (e.g. between 1 mg and 10 mg) of (+)-α-dihydrotetrabenazine succinate and a pharmaceutically acceptable excipient.        A unit dosage form comprising from 1 mg to 7.5 mg (e.g. between 1 mg and 7.5 mg) of (+)-α-dihydrotetrabenazine succinate and a pharmaceutically acceptable excipient.        A unit dosage form comprising from 3 mg to 20 mg (e.g. between 3 mg and 20 mg) of (+)-α-dihydrotetrabenazine succinate and a pharmaceutically acceptable excipient.        A unit dosage form comprising from 2 mg to 15 mg (e.g. between 2 mg and 15 mg) of (+)-α-dihydrotetrabenazine succinate and a pharmaceutically acceptable excipient.        A unit dosage form comprising from 3 mg to 15 mg (e.g. between 3 mg and 15 mg) of (+)-α-dihydrotetrabenazine succinate and a pharmaceutically acceptable excipient.        A unit dosage form comprising from 4 mg to 15 mg (e.g. between 4 mg and 15 mg) of (+)-α-dihydrotetrabenazine succinate and a pharmaceutically acceptable excipient.        A unit dosage form comprising from 5 mg to 15 mg (e.g. between 5 mg and 15 mg) of (+)-α-dihydrotetrabenazine succinate and a pharmaceutically acceptable excipient.        A unit dosage form comprising approximately 0.5 mg of (+)-α-dihydrotetrabenazine succinate and a pharmaceutically acceptable excipient.        A unit dosage form comprising approximately 1 mg of (+)-α-dihydrotetrabenazine succinate and a pharmaceutically acceptable excipient.        A unit dosage form comprising approximately 2 mg of (+)-α-dihydrotetrabenazine succinate and a pharmaceutically acceptable excipient.        A unit dosage form comprising approximately 3 mg of (+)-α-dihydrotetrabenazine succinate and a pharmaceutically acceptable excipient.        A unit dosage form comprising approximately 4 mg of (+)-α-dihydrotetrabenazine succinate and a pharmaceutically acceptable excipient.        A unit dosage form comprising approximately 5 mg of (+)-α-dihydrotetrabenazine succinate and a pharmaceutically acceptable excipient.        A unit dosage form comprising approximately 7.5 mg of (+)-α-dihydrotetrabenazine succinate and a pharmaceutically acceptable excipient.        A unit dosage form comprising approximately 10 mg of (+)-α-dihydrotetrabenazine succinate and a pharmaceutically acceptable excipient.        A unit dosage form comprising approximately 12.5 mg of (+)-α-dihydrotetrabenazine succinate and a pharmaceutically acceptable excipient.        A unit dosage form comprising approximately 15 mg of (+)-α-dihydrotetrabenazine succinate and a pharmaceutically acceptable excipient.        
The unit dosage forms may be administered orally and may be capsules or tablets.
The unit dosage forms defined and described above are typically for use in the treatment of a hyperkinetic movement disorder such as Huntington's disease, hemiballismus, senile chorea, tic disorders, tardive dyskinesia, dystonia and Tourette's syndrome.
The invention also provides:                (+)-α-dihydrotetrabenazine succinate for use in a method for the treatment of a movement disorder (e.g. a hyperkinetic movement disorder), wherein the treatment comprises administering to a subject an amount of (+)-α-dihydrotetrabenzine succinate between 1 mg and 30 mg per day.        A method of treatment of a movement disorder (e.g. a hyperkinetic movement disorder) in a subject in need thereof (e.g. a mammalian subject such as a human), which treatment comprises administering to the subject an amount of (+)-α-dihydrotetrabenazine succinate between 1 mg and 30 mg per day.        The use of (+)-α-dihydrotetrabenazine succinate for the manufacture of a medicament for the treatment of a movement disorder (e.g. a hyperkinetic movement disorder), which treatment comprises administering to the subject an amount of (+)-α-dihydrotetrabenazine succinate between 1 mg and 30 mg per day.        (+)-α-dihydrotetrabenazine succinate for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of (+)-α-dihydrotetrabenazine succinate between 2 mg and 30 mg per day.        (+)-α-dihydrotetrabenazine succinate for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of (+)-α-dihydrotetrabenazine succinate between 3 mg and 30 mg per day.        (+)-α-dihydrotetrabenazine succinate for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of (+)-α-dihydrotetrabenazine succinate between 2 mg and 20 mg per day.        (+)-α-dihydrotetrabenazine succinate for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of (+)-α-dihydrotetrabenazine succinate between 3 mg and 20 mg per day.        (+)-α-dihydrotetrabenazine succinate for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of (+)-α-dihydrotetrabenazine succinate between 5 mg and 20 mg per day.        (+)-α-dihydrotetrabenazine succinate for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of (+)-α-dihydrotetrabenazine of approximately 7.5 mg per day.        (+)-α-dihydrotetrabenazine succinate for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of (+)-α-dihydrotetrabenazine succinate of approximately 10 mg per day.        (+)-α-dihydrotetrabenazine succinate for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of (+)-α-dihydrotetrabenazine succinate of approximately 12.5 mg per day.        (+)-α-dihydrotetrabenazine succinate for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of (+)-α-dihydrotetrabenazine succinate of approximately 15 mg per day.        (+)-α-dihydrotetrabenazine succinate for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of (+)-α-dihydrotetrabenazine succinate of approximately 20 mg per day.        
In each case, the quantity of (+)-α-dihydrotetrabenazine succinate specified may be administered once per day or in several (e.g. two) doses per day.
In some embodiments, the quantity of (+)-α-dihydrotetrabenazine succinate specified is administered once daily.
The administration of (+)-α-dihydrotetrabenazine succinate typically forms part of a chronic treatment regime. The (+)-α-dihydrotetrabenazine succinate may therefore be administered to a patient for a treatment period of at least a week, more usually at least two weeks, or at least a month, and typically longer than a month. Where a patient is shown to respond well to treatment, the period of treatment can be longer than six months and may extend over a period of years.
The chronic treatment regime may involve the administration of the (+)-α-dihydrotetrabenazine succinate every day, or the treatment regime may include days when no (+)-α-dihydrotetrabenazine succinate is administered.
The dosage administered to the subject may vary during the treatment period. For example, the initial dosage may be increased or decreased depending on the subject's response to the treatment. A subject may, for example, be given an initial low dose to test the subject's tolerance towards the (+)-α-dihydrotetrabenazine succinate, and the dosage thereafter increased as necessary up to a maximum daily intake of 30 mg. Alternatively, an initial daily dosage administered to the patient may be selected so as to give an estimated desired degree of VMAT2 blockage, following which a lower maintenance dose may be given for the remainder of the treatment period, with the option of increasing the dosage should the subject's response to the treatment indicate that an increase is necessary.
Thus, the invention also provides a method of treating a movement disorder in a subject in need thereof, and (+)-α-dihydrotetrabenazine succinate for use in the method;
which method comprises the steps of:    (a) administering to the subject an initial daily dosage of (+)-α-dihydrotetrabenazine succinate, wherein the initial daily dosage is an amount of (+)-α-dihydrotetrabenazine succinate corresponding to from 0.5 mg to 5 mg of (+)-α-dihydrotetrabenazine free base;    (b) carrying out a clinical evaluation of the subject for efficacy and side effects arising from the treatment;    (c) where the clinical evaluation (b) has established that an increased daily dosage of (+)-α-dihydrotetrabenazine succinate is desirable, administering an increased daily dosage which is greater than the initial daily dosage by an incremental amount of (+)-α-dihydrotetrabenazine succinate thereof corresponding to from 0.5 mg to 5 mg of (+)-α-dihydrotetrabenazine free base; or, where the clinical evaluation has established that an increased daily dosage is not desirable, either maintaining the initial daily dosage, reducing the dosage, or discontinuing the treatment;    (d) where an increased daily dosage has been administered, carrying out a further clinical evaluation of the subject for efficacy and side effects arising from the treatment with the increased daily dosage;    (e) where the further clinical evaluation (d) has established that a further increased daily dosage of (+)-α-dihydrotetrabenazine succinate is desirable, administering a further increased daily dosage which is greater than an immediately preceding daily dosage by an incremental amount of (+)-α-dihydrotetrabenazine succinate corresponding to from 0.5 mg to 5 mg of (+)-α-dihydrotetrabenazine free base; or, where the clinical evaluation has established that a further increased daily dosage is not desirable, maintaining the immediately preceding daily dosage, reducing the immediately preceding dosage or discontinuing the treatment; and    (f) optionally repeating steps (d) and (e) as often as desired until an optimum daily dosage is reached.
In particular embodiments of the foregoing method, there are provided:
A method (or (+)-α-dihydrotetrabenazine succinate for use in the method) wherein the initial daily dosage of (+)-α-dihydrotetrabenazine succinate, is an amount corresponding to from 0.5 mg to 3 mg of (+)-α-dihydrotetrabenazine free base.
A method (or (+)-α-dihydrotetrabenazine succinate for use in the method) wherein the initial daily dosage of (+)-α-dihydrotetrabenazine succinate, is an amount corresponding to from 0.5 mg to 2 mg of (+)-α-dihydrotetrabenazine free base.
A method (or (+)-α-dihydrotetrabenazine succinate for use in the method) wherein the initial daily dosage of (+)-α-dihydrotetrabenazine succinate, is an amount corresponding to 0.5 mg, 1 mg, 1.5 mg, or 2 mg of (+)-α-dihydrotetrabenazine free base.
A method (or (+)-α-dihydrotetrabenazine succinate for use in the method) wherein the initial daily dosage of (+)-α-dihydrotetrabenazine succinate, is an amount corresponding to 0.5 mg of (+)-α-dihydrotetrabenazine free base.
A method (or (+)-α-dihydrotetrabenazine succinate for use in the method) wherein the initial daily dosage of (+)-α-dihydrotetrabenazine succinate, is an amount corresponding to 1 mg of (+)-α-dihydrotetrabenazine free base.
A method (or (+)-α-dihydrotetrabenazine succinate for use in the method) wherein the initial daily dosage of (+)-α-dihydrotetrabenazine succinate, is an amount corresponding to 1.5 mg of (+)-α-dihydrotetrabenazine free base.
A method (or (+)-α-dihydrotetrabenazine succinate for use in the method) wherein the initial daily dosage of (+)-α-dihydrotetrabenazine succinate, is an amount corresponding to 2 mg of (+)-α-dihydrotetrabenazine free base.
A method (or (+)-α-dihydrotetrabenazine succinate for use in the method) wherein the increased daily dosage in step (c) is an amount which is greater than the initial daily dosage by an incremental amount of (+)-α-dihydrotetrabenazine succinate corresponding to from 0.5 mg to 3 mg of (+)-α-dihydrotetrabenazine free base.
A method (or (+)-α-dihydrotetrabenazine succinate for use in the method) wherein the increased daily dosage in step (c) is an amount which is greater than the initial daily dosage by an incremental amount of (+)-α-dihydrotetrabenazine succinate corresponding to from 0.5 mg to 2 mg of (+)-α-dihydrotetrabenazine free base.
A method (or (+)-α-dihydrotetrabenazine succinate for use in the method) wherein the increased daily dosage in step (c) is an amount which is greater than the initial daily dosage by an incremental amount of (+)-α-dihydrotetrabenazine succinate corresponding to 0.5 mg, 1 mg, 1.5 mg, or 2 mg of (+)-α-dihydrotetrabenazine free base.
A method (or (+)-α-dihydrotetrabenazine succinate for use in the method) wherein the increased daily dosage in step (c) is an amount which is greater than the initial daily dosage by an incremental amount of (+)-α-dihydrotetrabenazine succinate corresponding to 0.5 mg of (+)-α-dihydrotetrabenazine free base.
A method (or (+)-α-dihydrotetrabenazine succinate for use in the method) wherein the increased daily dosage in step (c) is an amount which is greater than the initial daily dosage by an incremental amount of (+)-α-dihydrotetrabenazine succinate corresponding to 1 mg of (+)-α-dihydrotetrabenazine free base.
A method (or (+)-α-dihydrotetrabenazine succinate for use in the method) wherein the increased daily dosage in step (c) is an amount which is greater than the initial daily dosage by an incremental amount of (+)-α-dihydrotetrabenazine succinate corresponding to 1.5 mg of (+)-α-dihydrotetrabenazine free base.
A method (or (+)-α-dihydrotetrabenazine succinate for use in the method) wherein the increased daily dosage in step (c) is an amount which is greater than the initial daily dosage by an incremental amount of (+)-α-dihydrotetrabenazine succinate corresponding to 2 mg of (+)-α-dihydrotetrabenazine free base.
A method (or (+)-α-dihydrotetrabenazine succinate for use in the method) wherein the further increased daily dosage in step (e) is greater than an immediately preceding daily dosage by an incremental amount of (+)-α-dihydrotetrabenazine succinate corresponding to from 0.5 mg to 3 mg of (+)-α-dihydrotetrabenazine free base.
A method (or (+)-α-dihydrotetrabenazine succinate for use in the method) wherein the further increased daily dosage in step (e) is greater than an immediately preceding daily dosage by an incremental amount of (+)-α-dihydrotetrabenazine succinate corresponding to from 0.5 mg to 2 mg of (+)-α-dihydrotetrabenazine free base.
A method (or (+)-α-dihydrotetrabenazine succinate for use in the method) wherein the further increased daily dosage in step (e) is greater than an immediately preceding daily dosage by an incremental amount of (+)-α-dihydrotetrabenazine succinate corresponding to 0.5 mg, 1 mg, 1.5 mg, or 2 mg of (+)-α-dihydrotetrabenazine free base.
A method (or (+)-α-dihydrotetrabenazine succinate for use in the method) wherein the further increased daily dosage in step (e) is greater than an immediately preceding daily dosage by an incremental amount of (+)-α-dihydrotetrabenazine succinate corresponding to 0.5 mg of (+)-α-dihydrotetrabenazine free base.
A method (or (+)-α-dihydrotetrabenazine succinate for use in the method) wherein the further increased daily dosage in step (e) is greater than an immediately preceding daily dosage by an incremental amount of (+)-α-dihydrotetrabenazine succinate corresponding to 1 mg of (+)-α-dihydrotetrabenazine free base.
A method (or (+)-α-dihydrotetrabenazine succinate for use in the method) wherein the further increased daily dosage in step (e) is greater than an immediately preceding daily dosage by an incremental amount of (+)-α-dihydrotetrabenazine succinate corresponding to 1.5 mg of (+)-α-dihydrotetrabenazine free base.
A method (or (+)-α-dihydrotetrabenazine succinate for use in the method) wherein the further increased daily dosage in step (e) is greater than an immediately preceding daily dosage by an incremental amount of (+)-α-dihydrotetrabenazine succinate corresponding to 2 mg of (+)-α-dihydrotetrabenazine free base.
A method (or (+)-α-dihydrotetrabenazine succinate for use in the method) wherein the treatment comprises the administration of a maximum (e.g. optimized) daily dosage of (+)-α-dihydrotetrabenazine succinate, which is an amount corresponding to no greater than 20 mg of (+)-α-dihydrotetrabenazine free base.
A method (or (+)-α-dihydrotetrabenazine succinate for use in the method) wherein the treatment comprises the administration of a maximum (e.g. optimized) daily dosage of (+)-α-dihydrotetrabenazine succinate, which is an amount corresponding to no greater than 17.5 mg of (+)-α-dihydrotetrabenazine free base.
A method (or (+)-α-dihydrotetrabenazine succinate for use in the method) wherein the treatment comprises the administration of a maximum (e.g. optimized) daily dosage of (+)-α-dihydrotetrabenazine succinate, which is an amount corresponding to no greater than 15 mg of (+)-α-dihydrotetrabenazine free base.
A method (or (+)-α-dihydrotetrabenazine succinate for use in the method) wherein the treatment comprises the administration of a maximum (e.g. optimized) daily dosage of (+)-α-dihydrotetrabenazine succinate, which is an amount corresponding to no greater than 12.5 mg of (+)-α-dihydrotetrabenazine free base.
A method (or (+)-α-dihydrotetrabenazine succinate for use in the method) wherein the treatment comprises the administration of a maximum (e.g. optimized) daily dosage of (+)-α-dihydrotetrabenazine succinate, which is an amount corresponding to no greater than 10 mg of (+)-α-dihydrotetrabenazine free base.
A method (or (+)-α-dihydrotetrabenazine succinate for use in the method) wherein the treatment comprises the administration of a maximum (e.g. optimized) daily dosage of (+)-α-dihydrotetrabenazine succinate, which is an amount corresponding to no greater than 9 mg of (+)-α-dihydrotetrabenazine free base.
A method (or (+)-α-dihydrotetrabenazine succinate for use in the method) wherein the treatment comprises the administration of a maximum (e.g. optimized) daily dosage of (+)-α-dihydrotetrabenazine succinate, which is an amount corresponding to no greater than 8 mg of (+)-α-dihydrotetrabenazine free base.
A method (or (+)-α-dihydrotetrabenazine succinate for use in the method) wherein the treatment comprises the administration of a maximum (e.g. optimized) daily dosage of (+)-α-dihydrotetrabenazine succinate, which is an amount corresponding to no greater than 7.5 mg of (+)-α-dihydrotetrabenazine free base.
A method (or (+)-α-dihydrotetrabenazine succinate for use in the method) wherein the treatment comprises the administration of a maximum (e.g. optimized) daily dosage of (+)-α-dihydrotetrabenazine succinate, which is an amount corresponding to no greater than 7 mg of (+)-α-dihydrotetrabenazine free base.
A method (or (+)-α-dihydrotetrabenazine succinate for use in the method) wherein the treatment comprises the administration of a maximum (e.g. optimized) daily dosage of (+)-α-dihydrotetrabenazine succinate, which is an amount corresponding to no greater than 6 mg of (+)-α-dihydrotetrabenazine free base.
A method (or (+)-α-dihydrotetrabenazine succinate for use in the method) wherein the treatment comprises the administration of a maximum (e.g. optimized) daily dosage of (+)-α-dihydrotetrabenazine succinate, which is an amount corresponding to no greater than 5 mg of (+)-α-dihydrotetrabenazine free base.
A method (or (+)-α-dihydrotetrabenazine succinate for use in the method) wherein the treatment comprises the administration of a maximum (e.g. optimized) daily dosage of (+)-α-dihydrotetrabenazine succinate, which is an amount corresponding to no greater than 4 mg of (+)-α-dihydrotetrabenazine free base.
A method (or (+)-α-dihydrotetrabenazine succinate for use in the method) wherein the treatment comprises the administration of a maximum (e.g. optimized) daily dosage of (+)-α-dihydrotetrabenazine succinate, which is an amount corresponding to no greater than 3 mg of (+)-α-dihydrotetrabenazine free base.
A method (or (+)-α-dihydrotetrabenazine succinate for use in the method) wherein the treatment comprises the administration of a maximum (e.g. optimized) daily dosage of (+)-α-dihydrotetrabenazine succinate, which is an amount corresponding to no greater than 2.5 mg of (+)-α-dihydrotetrabenazine free base.
The quantity of (+)-α-dihydrotetrabenazine succinate required to achieve the desired therapeutic effect may be dependent on the weight of the subject to be treated. The quantities of (+)-α-dihydrotetrabenazine succinate administered to the subject can be expressed as the number of mg/kg, where “mg” refers to the weight of active compound (i.e. the (+)-α-dihydrotetrabenazine free base component of the salt) and “kg” refers to the weight of the subject to be treated. The appropriate dosage amount can therefore be calculated by multiplying the mg/kg amount by the weight of the subject to be treated. Accordingly, the invention also provides:                (+)-α-dihydrotetrabenazine succinate for use in a method for the treatment of a movement disorder, wherein the treatment comprises administering to a subject an amount of (+)-α-dihydrotetrabenazine succinate salt corresponding to between 0.01 mg/kg and 0.5 mg/kg per day of (+)-α-dihydrotetrabenazine free base provided that the total amount of (+)-α-dihydrotetrabenazine succinate administered per day is in the range from 1 mg to 30 mg (e.g. from 1 mg to 20 mg).        A method of treatment of a movement disorder in a subject in need thereof (e.g. a mammalian subject such as a human), which treatment comprises administering to the subject an amount of (+)-α-dihydrotetrabenazine succinate corresponding to between 0.01 mg/kg and 0.5 mg/kg per day of (+)-α-dihydrotetrabenazine free base, provided that the total amount of (+)-α-dihydrotetrabenazine succinate administered per day is in the range from 1 mg to 30 mg (e.g. from 1 mg to 20 mg).        The use of (+)-α-dihydrotetrabenazine succinate for the manufacture of a medicament for the treatment of a movement disorder, which treatment comprises administering to the subject an amount of (+)-α-dihydrotetrabenazine succinate corresponding to between 0.01 mg/kg and 0.5 mg/kg (+)-α-dihydrotetrabenazine free base, provided that the total amount of (+)-α-dihydrotetrabenazine succinate administered per day is in the range from 1 mg to 30 mg (e.g. from 1 mg to 20 mg).        
In further embodiments, there is provided:                (+)-α-dihydrotetrabenazine succinate for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of (+)-α-dihydrotetrabenazine succinate corresponding to between 0.01 mg/kg and 0.3 mg/kg of (+)-α-dihydrotetrabenazine free base per day, provided that the total amount of (+)-α-dihydrotetrabenazine succinate administered per day is in the range from 0.5 mg to 20 mg (e.g. 1 mg to 20 mg).        (+)-α-dihydrotetrabenazine succinate for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of (+)-α-dihydrotetrabenazine succinate corresponding to between 0.02 mg/kg and 0.3 mg/kg of (+)-α-dihydrotetrabenazine free base per day, provided that the total amount of (+)-α-dihydrotetrabenazine succinate administered per day is in the range from 0.5 mg to 20 mg (e.g. 1 mg to 20 mg).        (+)-α-dihydrotetrabenazine succinate for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of (+)-α-dihydrotetrabenazine succinate corresponding to between 0.03 mg/kg and 0.3 mg/kg of (+)-α-dihydrotetrabenazine free base, provided that the total amount of (+)-α-dihydrotetrabenazine succinate administered per day is in the range from 0.5 mg to 20 mg (e.g. 1 mg to 20 mg).        (+)-α-dihydrotetrabenazine succinate for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of (+)-α-dihydrotetrabenazine succinate corresponding to between 0.04 mg/kg and 0.3 mg/kg of (+)-α-dihydrotetrabenazine free base, provided that the total amount of (+)-α-dihydrotetrabenazine succinate administered per day is in the range from 0.5 mg to 20 mg (e.g. 1 mg to 20 mg).        (+)-α-dihydrotetrabenazine succinate for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of (+)-α-dihydrotetrabenazine succinate corresponding to between 0.05 mg/kg and 0.3 mg/kg of (+)-α-dihydrotetrabenazine free base, provided that the total amount of (+)-α-dihydrotetrabenazine succinate administered per day is in the range from 0.5 mg to 20 mg (e.g. 1 mg to 20 mg).        (+)-α-dihydrotetrabenazine succinate for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of (+)-α-dihydrotetrabenazine succinate corresponding to between 0.02 mg/kg and 0.2 mg/kg of (+)-α-dihydrotetrabenazine free base per day, provided that the total amount of (+)-α-dihydrotetrabenazine succinate administered per day is in the range from 0.5 mg to 20 mg (e.g. 1 mg to 20 mg).        (+)-α-dihydrotetrabenazine succinate for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of (+)-α-dihydrotetrabenazine succinate corresponding to between 0.03 mg/kg and 0.2 mg/kg of (+)-α-dihydrotetrabenazine free base, provided that the total amount of (+)-α-dihydrotetrabenazine succinate administered per day is in the range from 0.5 mg to 20 mg (e.g. 1 mg to 20 mg).        (+)-α-dihydrotetrabenazine succinate for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of (+)-α-dihydrotetrabenazine succinate corresponding to between 0.04 mg/kg and 0.2 mg/kg of (+)-α-dihydrotetrabenazine free base, provided that the total amount of (+)-α-dihydrotetrabenazine succinate administered per day is in the range from 0.5 mg to 20 mg (e.g. 1 mg to 20 mg).        (+)-α-dihydrotetrabenazine succinate for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of (+)-α-dihydrotetrabenazine succinate corresponding to between 0.05 mg/kg and 0.2 mg/kg of (+)-α-dihydrotetrabenazine free base, provided that the total amount of (+)-α-dihydrotetrabenazine free base administered per day is in the range from 0.5 mg to 20 mg (e.g. 1 mg to 20 mg).        (+)-α-dihydrotetrabenazine succinate for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of (+)-α-dihydrotetrabenazine succinate corresponding to between 0.02 mg/kg and 0.1 mg/kg of (+)-α-dihydrotetrabenazine free base per day, provided that the total amount of (+)-α-dihydrotetrabenazine succinate administered per day is in the range from 0.5 mg to 20 mg (e.g. 1 mg to 20 mg).        (+)-α-dihydrotetrabenazine succinate for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of (+)-α-dihydrotetrabenazine succinate corresponding to between 0.03 mg/kg and 0.1 mg/kg of (+)-α-dihydrotetrabenazine free base, provided that the total amount of (+)-α-dihydrotetrabenazine succinate administered per day is in the range from 0.5 mg to 20 mg (e.g. 1 mg to 20 mg).        (+)-α-dihydrotetrabenazine succinate for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of (+)-α-dihydrotetrabenazine succinate corresponding to between 0.04 mg/kg and 0.1 mg/kg of (+)-α-dihydrotetrabenazine free base, provided that the total amount of (+)-α-dihydrotetrabenazine succinate administered per day is in the range from 0.5 mg to 20 mg (e.g. 1 mg to 20 mg).        (+)-α-dihydrotetrabenazine succinate for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of (+)-α-dihydrotetrabenazine succinate corresponding to between 0.05 mg/kg and 0.1 mg/kg of (+)-α-dihydrotetrabenazine free base, provided that the total amount of (+)-α-dihydrotetrabenazine succinate administered per day is in the range from 0.5 mg to 20 mg (e.g. 1 mg to 20 mg).        (+)-α-dihydrotetrabenazine succinate for use, a method or a use as described herein, wherein the use or method comprises administering to the subject an effective amount of (+)-α-dihydrotetrabenazine succinate wherein:                    (i) when the subject has a weight of 30 kg to 50 kg, the said effective amount is a daily amount of (+)-α-dihydrotetrabenazine or a pharmaceutically acceptable salt thereof corresponding to from 2 mg to 7.5 mg of (+)-α-dihydrotetrabenazine free base;            (ii) when the subject has a weight of 50 kg to 75 kg, the said effective amount is a daily amount of (+)-α-dihydrotetrabenazine or a pharmaceutically acceptable salt thereof corresponding to from 5 mg to 10 mg of (+)-α-dihydrotetrabenazine free base;            (iii) when the subject has a weight of 75 kg to 95 kg, the said effective amount is a daily amount of (+)-α-dihydrotetrabenazine or a pharmaceutically acceptable salt thereof corresponding to from 7.5 mg to 15 mg of (+)-α-dihydrotetrabenazine free base; or            (iv) when the subject has a weight of greater than 95 kg, the said effective amount is a daily amount of (+)-α-dihydrotetrabenazine or a pharmaceutically acceptable salt thereof corresponding to from 15 mg to 20 mg of (+)-α-dihydrotetrabenazine free base the amount of (+)-α-dihydrotetrabenazine administered per day is from 15 mg to 20 mg.                        
The present inventors have found that plasma levels of (+)-α-dihydrotetrabenazine required for effective treatment of hyperkinetic movement disorders can be considerably lower than the plasma levels achieved by administration of Valbenazine as described in WO 2015/171802.
Accordingly, in a further aspect, the invention provides:                (+)-α-dihydrotetrabenazine succinate, or a pharmaceutically acceptable salt thereof, for use in a method of treatment of a movement disorder; or        A method of treatment of a movement disorder in a subject in need thereof (e.g. a mammalian subject such as a human); or        The use of (+)-α-dihydrotetrabenazine succinate for the manufacture of a medicament for the treatment of a movement disorderwherein the treatment comprises administering to a subject a therapeutically effective amount of the (+)-α-dihydrotetrabenazine succinate in an amount sufficient to achieve an average blood plasma Cavg concentration of (+)-α-dihydrotetrabenazine free base, where measured over a period of three hours, in the range from 2 ng/ml to 15 ng/ml.        
In one embodiment, the invention provides:                (+)-α-dihydrotetrabenazine succinate for use in a method of treatment of a movement; or        A method of treatment of a movement disorder in a subject in need thereof (e.g. a mammalian subject such as a human); or        The use of (+)-α-dihydrotetrabenazine succinate for the manufacture of a medicament for the treatment of a movement disorder;wherein the treatment comprises administering to a subject a therapeutically effective amount of the (+)-α-dihydrotetrabenazine succinate in an amount sufficient to achieve an average blood plasma Cavg concentration of (+)-α-dihydrotetrabenazine free base, when measured over a period of three hours, in the range from 3 ng/ml to 15 ng/ml.        
Complete blocking of the VMAT2 proteins is considered undesirable as this can lead to unwanted side effects, such as Parkinsonism. The present invention provides plasma levels of (+)-α-dihydrotetrabenazine that are sufficient to give effective treatment of movement disorders but do not block the VMAT2 proteins to an extent that causes Parkinsonism and similar side effects. The levels of VMAT2 blocking can be determined by competitive binding studies using Positron Emission Tomography (PET). By co-administering a radioactive ligand with the compound of interest at various concentrations, the proportion of binding sites occupied can be determined (see for example, Matthews et al., “Positron emission tomography molecular imaging for drug development”, Br. J. Clin. Pharmacol., 73:2, 175-186). Accordingly, the invention also provides:                (+)-α-dihydrotetrabenazine succinate for use in a method for the treatment of a movement disorder, wherein the treatment comprises administering to a subject an amount of (+)-α-dihydrotetrabenazine succinate sufficient to cause a level of blocking of up to 90% of the VMAT2 proteins in the subject.        A method of treatment of a movement disorder in a subject in need thereof (e.g. a mammalian subject such as a human), which treatment comprises administering to the subject an amount of (+)-α-dihydrotetrabenazine succinate sufficient to cause a level of blocking of up to 90% of the VMAT2 proteins in the subject.        The use of (+)-α-dihydrotetrabenazine succinate for the manufacture of a medicament for the treatment of a movement disorder, which treatment comprises administering to the subject an amount of (+)-α-dihydrotetrabenazine succinate sufficient to cause a level of blocking of up to 90% of the VMAT2 proteins in the subject.        
In further embodiments, there is provided:                (+)-α-dihydrotetrabenazine succinate for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of (+)-α-dihydrotetrabenazine succinate sufficient to cause a level of blocking of up to 85% of the VMAT2 proteins in the subject.        (+)-α-dihydrotetrabenazine succinate for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of (+)-α-dihydrotetrabenazine succinate sufficient to cause a level of blocking of up to 80% of the VMAT2 proteins in the subject.        (+)-α-dihydrotetrabenazine succinate for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of (+)-α-dihydrotetrabenazine succinate sufficient to cause a level of blocking of up to 75% of the VMAT2 proteins in the subject.        (+)-α-dihydrotetrabenazine succinate for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of (+)-α-dihydrotetrabenazine succinate sufficient to cause a level of blocking of up to 70% of the VMAT2 proteins in the subject.        (+)-α-dihydrotetrabenazine succinate for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of (+)-α-dihydrotetrabenazine succinate sufficient to cause a level of blocking of from 25% to 85% of the VMAT2 proteins in the subject.        (+)-α-dihydrotetrabenazine succinate for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of (+)-α-dihydrotetrabenazine succinate sufficient to cause a level of blocking of from 30% to 80% of the VMAT2 proteins in the subject.        (+)-α-dihydrotetrabenazine succinate for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of (+)-α-dihydrotetrabenazine succinate sufficient to cause a level of blocking of from 35% to 75% of the VMAT2 proteins in the subject.        (+)-α-dihydrotetrabenazine succinate for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of (+)-α-dihydrotetrabenazine succinate sufficient to cause a level of blocking of from 35% to 70% of the VMAT2 proteins in the subject.        (+)-α-dihydrotetrabenazine succinate for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of (+)-α-dihydrotetrabenazine succinate sufficient to cause a level of blocking of from 40% to 75% of the VMAT2 proteins in the subject.        (+)-α-dihydrotetrabenazine succinate for use, a method or a use as described herein, wherein the treatment comprises administering to the subject in need thereof, wherein the method comprising administering to a subject an amount of (+)-α-dihydrotetrabenazine succinate sufficient to cause a level of blocking of from 45% to 75% of the VMAT2 proteins in the subject.        (+)-α-dihydrotetrabenazine succinate for use, a method or a use as described herein, wherein the treatment comprises administering to the subject in need thereof, wherein the method comprising administering to a subject an amount of (+)-α-dihydrotetrabenazine succinate sufficient to cause a level of blocking of from 35% to 80% of the VMAT2 proteins in the subject.        (+)-α-dihydrotetrabenazine succinate for use, a method or a use as described herein, wherein the treatment comprises administering to the subject in need thereof, wherein the method comprising administering to a subject an amount of (+)-α-dihydrotetrabenazine succinate sufficient to cause a level of blocking of from 40% to 80% of the VMAT2 proteins in the subject.        (+)-α-dihydrotetrabenazine succinate for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of (+)-α-dihydrotetrabenazine succinate sufficient to cause a level of blocking of from 45% to 80% of the VMAT2 proteins in the subject.        (+)-α-dihydrotetrabenazine succinate for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of (+)-α-dihydrotetrabenazine succinate sufficient to cause a level of blocking of from 50% to 80% of the VMAT2 proteins in the subject.        (+)-α-dihydrotetrabenazine succinate for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of (+)-α-dihydrotetrabenazine succinate sufficient to cause a level of blocking of from 50% to 85% of the VMAT2 proteins in the subject.        (+)-α-dihydrotetrabenazine succinate for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of (+)-α-dihydrotetrabenazine succinate sufficient to cause a level of blocking of from 55% to 80% of the VMAT2 proteins in the subject.        (+)-α-dihydrotetrabenazine succinate for use, a method or a use as described herein, wherein the treatment comprises administering to the subject an amount of (+)-α-dihydrotetrabenazine succinate sufficient to cause a level of blocking of VMAT2 proteins in the subject of between 30% and 70%.        (+)-α-dihydrotetrabenazine succinate for use, a method or a use as described herein, wherein the treatment comprises administering to the subject in need thereof, wherein the method comprising administering to a subject an amount of (+)-α-dihydrotetrabenazine succinate sufficient to cause a blocking level of VMAT2 proteins in the subject of between 30% and 65%.        (+)-α-dihydrotetrabenazine succinate for use, a method or a use as described herein, wherein the treatment comprises administering to the subject in need thereof, wherein the method comprising administering to a subject an amount of (+)-α-dihydrotetrabenazine succinate sufficient to cause a blocking level of VMAT2 proteins in the subject of between 30% and 60%.        (+)-α-dihydrotetrabenazine succinate for use, a method or a use as described herein, wherein the treatment comprises administering to the subject in need thereof, wherein the method comprising administering to a subject an amount of (+)-α-dihydrotetrabenazine succinate sufficient to cause a level blocking of VMAT2 proteins in the subject of between 40% and 80%.        (+)-α-dihydrotetrabenazine succinate for use, a method or a use as described herein, wherein the treatment comprises administering to the subject in need thereof, wherein the method comprising administering to a subject an amount of (+)-α-dihydrotetrabenazine succinate sufficient to cause a level of blocking of VMAT2 proteins in the subject of between 40% and 75%.        (+)-α-dihydrotetrabenazine succinate for use, a method or a use as described herein, wherein the treatment comprises administering to the subject in need thereof, wherein the method comprising administering to a subject an amount of (+)-α-dihydrotetrabenazine succinate sufficient to cause a level of blocking of VMAT2 proteins in the subject of between 40% and 70%.        (+)-α-dihydrotetrabenazine succinate for use, a method or a use as described herein, wherein the treatment comprises administering to the subject in need thereof, wherein the method comprising administering to a subject an amount of (+)-α-dihydrotetrabenazine succinate sufficient to cause a level of blocking of VMAT2 proteins in the subject of between 40% and 65%.        (+)-α-dihydrotetrabenazine succinate for use, a method or a use as described herein, wherein the treatment comprises administering to the subject in need thereof, wherein the method comprising administering to a subject an amount of (+)-α-dihydrotetrabenazine succinate sufficient to cause a level of blocking of VMAT2 in the subject of between 40% and 60%.        
In each of the foregoing aspects and embodiments of the invention, the (+)-α-dihydrotetrabenazine succinate is typically not administered in combination with a therapeutically effective amount of amantadine. More particularly, in each of the foregoing aspects and embodiments of the invention, the (+)-α-dihydrotetrabenazine or pharmaceutically acceptable salt thereof is typically not administered in combination with any amount of amantadine.
The movement disorder can be a hyperkinetic movement disorder such as Huntington's disease, hemiballismus, senile chorea, tic disorders, tardive dyskinesia, dystonia, myoclonus and Tourette's syndrome. In one Embodiment, the movement disorder is Tourette's syndrome. In another embodiment, the movement disorder is tardive dyskinesia. In another embodiment, the movement disorder is Huntington's disease.
The term “treatment” as used herein in the context of treating a condition or disorder, pertains generally to treatment and therapy in which some desired therapeutic effect is achieved, for example, the inhibition of the progress of the condition, and includes a reduction in the rate of progress, a halt in the rate of progress, amelioration of the condition, diminishment or alleviation of at least one symptom associated or caused by the condition being treated and cure of the condition. When the hyperkinetic movement disorder being treated is Tourette's Syndrome, treatment of the disorder may pertain to a reduction of the incidence or severity of tics.
Isotopes
The (+)-α-dihydrotetrabenazine succinate may contain one or more isotopic substitutions, and a reference to a particular element includes within its scope all isotopes of the element. For example, a reference to hydrogen includes within its scope 1H, 2H (D), and 3H (T). Similarly, references to carbon and oxygen include within their scope respectively 11C, 12D, 13D and 14C and 16O and 18O.
Typically, the (+)-α-dihydrotetrabenazine succinate of the invention does not contain isotopes (such as 11O or 3H) in amounts higher than their natural abundance.
In one embodiment, the percentage of the total hydrogen atoms in the (+)-α-dihydrotetrabenazine succinate that are deuterium atoms is less than 2%, more typically less than 1%, more usually less than 0.1%, preferably less than 0.05% and most preferably no more than 0.02%.
In an analogous manner, a reference to a particular functional group also includes within its scope isotopic variations, unless the context indicates otherwise.
The isotopes may be radioactive or non-radioactive. In one embodiment of the invention, the (+)-α-dihydrotetrabenazine succinate contains no radioactive isotopes. Such compounds are preferred for therapeutic use. In another embodiment, however, the (+)-α-dihydrotetrabenazine succinate may contain one or more radioisotopes. Compounds containing such radioisotopes may be useful in a diagnostic context.
Solvates
(+)-α-Dihydrotetrabenazine succinate may form solvates.
Examples of solvates are solvates formed by the incorporation into the solid state structure (e.g. crystal structure) of the compounds of the invention of molecules of a non-toxic pharmaceutically acceptable solvent (referred to below as the solvating solvent). Examples of such solvents include water, alcohols (such as ethanol, isopropanol and butanol) and dimethylsulphoxide. Solvates can be prepared by recrystallising the compounds of the invention with a solvent or mixture of solvents containing the solvating solvent. Whether or not a solvate has been formed in any given instance can be determined by subjecting crystals of the compound to analysis using well known and standard techniques such as thermogravimetric analysis (TGE), differential scanning calorimetry (DSC) and X-ray crystallography.
The solvates can be stoichiometric or non-stoichiometric solvates.
Particular solvates are hydrates, and particular examples of hydrates include hemihydrates, monohydrates and dihydrates.
For a more detailed discussion of solvates and the methods used to make and characterise them, see Bryn et al., Solid-State Chemistry of Drugs, Second Edition, published by SSCI, Inc of West Lafayette, Ind., USA, 1999, ISBN 0-967-06710-3.
Alternatively, rather than existing as a hydrate, the (+)α-dihydrotetrabenazine succinate of the invention may be anhydrous. Therefore, in another embodiment, the (+)-α-dihydrotetrabenazine succinate is in an anhydrous form.
Methods for the Preparation of Dihydrotetrabenazine Succinate Salts
(+)-α-Dihydrotetrabenazine (compound of formula (I)) can be prepared from tetrabenazine according to the synthetic route shown in Scheme 1.

Racemic tetrabenazine (3-isobutyl-9,10-dimethyoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1,a]isoquinolin-2-one) containing the RR and SS isomers of tetrabenazine is reduced with sodium borohydride to afford a mixture of four dihydrotetrabenazine isomers of which a racemic mixture of the α-dihydrotetrabenazines (RRR and SSS isomers) constitutes the major product and a racemic mixture of the β-dihydrotetrabenazines (the SRR and RSS isomers) constitutes a minor product. The β-dihydrotetrabenazines can be removed during an initial purification procedure, for example by chromatography or recrystallization and then the racemic α-dihydrotetrabenazines resolved (e.g. by recrystallisation with di-p-toluoyl-L-tartaric acid or (R)-(−)-camphorsulfonic acid or by chiral chromatography), to afford (+)-α-dihydrotetrabenazine (I) ((2R, 3R, 11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1,a]isoquinolin-2-ol).
(+)-α-Dihydrotetrabenazine can also be prepared according to Yao et al., “Preparation and evaluation of tetrabenazine enantiomers and all eight stereoisomers of dihydrotetrabenazine as VMAT2 inhibitors”, Eur. J. Med. Chem., (2011), 46, pp. 1841-1848.
The (+)-α-dihydrotetrabenazine succinate salt can then be prepared by reacting the (+)-α-DHTBZ free base with succinic acid. The reaction is typically carried out in the presence of a solvent.
Accordingly, in a further aspect of the invention, there is provided a process for preparing a (+)-α-dihydrotetrabenazine succinate salt of the invention, which process comprises mixing (+)-α-dihydrotetrabenazine free base of the formula (I):
with succinic acid together with a solvent, allowing formation of the salt to take place, and isolating the (+)-α-dihydrotetrabenazine succinate salt.
In one embodiment, the process for preparing (+)-alpha-DHTBZ succinate salt comprises reacting the (+)-alpha-DHTBZ free base of Formula (II) and succinic acid together with a solvent to form a reaction mixture and then stirring the reaction mixture for a period of at least one hour, more typically at least 2 hours, or at least 4 hours, or at least 12 hours, for example at least 1 day.
The solvent may be a single solvent or may comprise a mixture of solvents. Generally the solvent will consist of or contain at least one polar aprotic solvent, examples being acetone and ethyl acetate.
In one embodiment, the solvent is selected from acetone, ethyl acetate and mixtures thereof.
In a particular embodiment, the solvent is acetone.
A preferred method of preparing (+)-α-dihydrotetrabenazine succinate salt comprises forming a slurry from (+)-α-dihydrotetrabenazine, succinic acid (e.g. at room temperature) and a non-aqueous solvent and stirring the slurry for a time period long enough to permit formation of the succinate salt. The time period is typically at least four hours, more usually at least six hours, or at least twelve hours, and in particular at least eighteen hours. A particular non-aqueous solvent for use in this method is acetone.
Pharmaceutical Formulations and Methods of Treatment
The pharmaceutical compositions of the invention can be in any form suitable for oral, parenteral, topical, intranasal, intrabronchial, ophthalmic, otic, rectal, intra-vaginal, or transdermal administration. Where the compositions are intended for parenteral administration, they can be formulated for intravenous, intramuscular, intraperitoneal, subcutaneous administration or for direct delivery into a target organ or tissue by injection, infusion or other means of delivery.
Pharmaceutical dosage forms suitable for oral administration include tablets, capsules, caplets, pills, lozenges, syrups, solutions, sprays, powders, granules, elixirs and suspensions, sublingual tablets, sprays, wafers or patches and buccal patches.
Pharmaceutical compositions containing (+)-α-dihydrotetrabenazine succinate can be formulated in accordance with known techniques, see for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa., USA.
Thus, tablet compositions can contain a unit dosage of active compound together with an inert diluent or carrier such as a sugar or sugar alcohol, e.g.; lactose, sucrose, sorbitol or mannitol; and/or a non-sugar derived diluent such as sodium carbonate, calcium phosphate, talc, calcium carbonate, or a cellulose or derivative thereof such as methyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose, and starches such as corn starch. Tablets may also contain such standard ingredients as binding and granulating agents such as polyvinylpyrrolidone, disintegrants (e.g. swellable crosslinked polymers such as crosslinked carboxymethylcellulose), lubricating agents (e.g. stearates), preservatives (e.g. parabens), antioxidants (e.g. BHT), buffering agents (for example phosphate or citrate buffers), and effervescent agents such as citrate/bicarbonate mixtures. Such excipients are well known and do not need to be discussed in detail here.
Capsule formulations may be of the hard gelatin or soft gelatin variety and can contain the active component in solid, semi-solid, or liquid form. Gelatin capsules can be formed from animal gelatin or synthetic or plant derived equivalents thereof.
The solid dosage forms (e.g.; tablets, capsules etc.) can be coated or un-coated, but typically have a coating, for example a protective film coating (e.g. a wax or varnish) or a release controlling coating. The coating (e.g. a Eudragit™ type polymer) can be designed to release the active component at a desired location within the gastro-intestinal tract. Thus, the coating can be selected so as to degrade under certain pH conditions within the gastrointestinal tract, thereby selectively release the compound in the stomach or in the ileum or duodenum.
Instead of, or in addition to, a coating, the drug can be presented in a solid matrix comprising a release controlling agent, for example a release delaying agent which may be adapted to selectively release the compound under conditions of varying acidity or alkalinity in the gastrointestinal tract. Alternatively, the matrix material or release retarding coating can take the form of an erodible polymer (e.g. a maleic anhydride polymer) which is substantially continuously eroded as the dosage form passes through the gastrointestinal tract.
Compositions for topical use include ointments, creams, sprays, patches, gels, liquid drops and inserts (for example intraocular inserts). Such compositions can be formulated in accordance with known methods.
Compositions for parenteral administration are typically presented as sterile aqueous or oily solutions or fine suspensions, or may be provided in finely divided sterile powder form for making up extemporaneously with sterile water for injection. Examples of formulations for rectal or intra-vaginal administration include pessaries and suppositories which may be, for example, formed from a shaped mouldable or waxy material containing the active compound.
Compositions for administration by inhalation may take the form of inhalable powder compositions or liquid or powder sprays, and can be administrated in standard form using powder inhaler devices or aerosol dispensing devices. Such devices are well known. For administration by inhalation, the powdered formulations typically comprise the active compound together with an inert solid powdered diluent such as lactose.
Compositions for administration by inhalation may take the form of inhalable powder compositions or liquid or powder sprays, and can be administrated in standard form using powder inhaler devices or aerosol dispensing devices. Such devices are well known. For administration by inhalation, the powdered formulations typically comprise the active compound together with an inert solid powdered diluent such as lactose.
Particular pharmaceutical compositions of the invention are compositions selected from:                Sublingual compositions;        Intranasal;        Pellets or tablets formulated to provide release kinetics corresponding to zero order release of the active compound;        Pellets or tablets formulated to provide first fast release followed by constant rate release (zero order) of the active compound;        Pellets or tablets formulated to provide a mixture of first order and zero order release of the active compound; and        Pellets or tablets formulated to provide a combination of zero order and first order release of the active compound; and optionally a further order of release of the active compound selected from second, third and fourth orders of release and combinations thereof.        
Pellets and tablets formulated to provide release kinetics of the types defined above can be prepared according to methods well known the skilled person; for example as described in Remington's Pharmaceutical Sciences (idem) and “Remington—The Science and Practice of Pharmacy, 21st edition, 2006, ISBN 0-7817-4673-6.
The compounds of the invention will generally be presented in unit dosage form and, as such, will typically contain an amount of compound sufficient to provide a desired level of biological activity. Such amounts are set out above.
The active compound will be administered to a subject (patient) in need thereof (for example a human or animal patient) in an amount sufficient to achieve the desired therapeutic effect, as described above.